SKIN CANCER (E TONGDEE AND O MARKOWITZ, SECTION EDITORS)

Updates on Treatment Approaches for Cutaneous Field Cancerization

Alisen Huang1& Julie K. Nguyen1

& Evan Austin1& Andrew Mamalis1 & Jared Jagdeo1

Published online: 19 July 2019# The Author(s) 2019

AbstractPurpose of Review Field cancerization describes the phenomenon that multiple heterogenous mutations may arise in an areaexposed to chronic carcinogenic stimuli. Advances in the understanding of cutaneous field cancerization have led to noveltherapeutic approaches to the management of actinic keratoses (AKs). Herein, we review the literature on the pathophysiologyand emerging research of field cancerization in dermatology.Recent Findings The classification systems for grading AK lesions are being refined with investigations focusing on their clinicalutility. There is a growing shift toward field-directed treatment for AKs as the importance of field cancerization becomes clearer.Current field-directed therapies are being optimized and novel therapeutic modalities are being studied.Summary Field cancerization underlies the transformation of photodamaged skin into AKs and potentially cutaneous squamouscell carcinoma (cSCC). Clinically meaningful classification systems for AKs are needed to better inform decisions regardingtreatment. As we learn more about the role of field characterization in photodamage, AKs, and cSCCs, therapeutic strategies arebecoming more field-directed rather than lesion-directed.

Keywords Field cancerization . Actinic keratosis . Cutaneous squamous cell carcinoma . Photodamage . Photodynamic therapy

Introduction

Field Cancerization Concept

Field cancerization describes the phenomenon that multipleheterogenous mutations may arise in an area exposed tochronic carcinogenic stimuli [1••]. As one or more cells un-dergo irreversible genetic changes that persist over multiplecycles of cell division, a dysplastic field emerges [1••].Invasive properties are not evident initially, but as somaticmutations accumulate from carcinogen exposure, subclonalproliferations may eventually induce carcinoma [1••, 2]. Theterm “field cancerization” was first coined and described in alandmark study by Slaughter et al. in 1953 in reference to

oropharyngeal squamous cell carcinoma (SCC) [3]. Areas ad-jacent to the tumor appeared grossly normal but histopatho-logic examination demonstrated dysplastic changes and fociof oropharyngeal SCC in situ [3]. The findings of discreteprimary tumors and islands of dysplastic epithelium suggestedthat the tumors had simultaneously developed independent ofeach other, rather than from the clonal proliferation of a singlemutant cell [2].

The concept of field cancerization is especially relevant indermatology, as it describes how actinic keratosis (AK) le-sions develop and subsequently transform into cutaneousSCC (cSCC), the second most common malignancy in theUS [4]. A committee of European dermatologists defined fieldcancerization as the anatomical area including or adjacent toAKs with visibly photodamaged skin, characterized by pig-mentary changes, rough texture, atrophy, or telangiectasia [5].

Field cancerization has significant therapeutic implicationsand clinical consequences in dermatology. AKs are typicallyviewed as precancerous; however, treatment of individual le-sions often does not address mutations in nearby cells thatmay be transforming into cancer [2]. AKs are one of the mostprevalent diagnoses in dermatology and are expected to in-crease with the aging population and increased exposure tosunlight [6]. In 2015, over 35 million cases of AKs were

Julie K. Nguyen and Evan Austin contributed equally to this work.

This article is part of the Topical Collection on Skin Cancer

* Jared Jagdeojrjagdeo@gmail.com

1 Department of Dermatology, Downstate Medical Center, StateUniversity of New York, 450 Clarkson Ave, Brooklyn, NY 11203,USA

Current Dermatology Reports (2019) 8:122–132https://doi.org/10.1007/s13671-019-00265-2

treated in the Medicare Part B fee-for-service population, upfrom 29.7 million in 2007, highlighting the treatment burdenof this condition [7]. AKs have been estimated to cost the UShealthcare system $920 million annually [8]. There is up to0.075% risk per lesion-year of AK transformation to cSCC,increasing to 2.57% at 4 years [9, 10].

Currently, there is no reliable method to discern AKs thatwill transform into cSCCs from those that will either remainbenign or resolve without treatment, complicating the treat-ment algorithm of AKs. Various approaches are being inves-tigated for this unanswered question including imaging tech-niques and genotyping [5, 11]. The Department of VeteransAffairs Topical Tretinoin Chemoprevention (VATTC) trial is a5-year multicenter clinical trial that followed individual AKlesions. By 1 year, 55% of AKs had regressed, and at 5 years,70% were not present [10]. Of note, some AKs not present atthe 1 year follow-up were present at later follow-up visits,which is consistent with the reported regression and recur-rence of AKs [10]. Of the primary cSCCs that were diagnosed,65% of those arose from lesions that were initially diagnosedas AKs [10]. Interestingly, 36% of basal cell carcinomas(BCCs) were diagnosed from lesions that were previouslydiagnosed as AKs, indicating that either BCCs and cSCCsmay share a common underlying pathogenesis or the initialAK diagnosis was incorrect [10]. Another study estimated thatapproximately 10% of AKs will undergo malignant transfor-mation into cSCC with the average time for conversion being24.6 months (range 2 to 65 months) [12]. Without interven-tion, resulting cSCC may subsequently lead to significanthealthcare expenditure, patient morbidity, and patient mortal-ity. In 2013, it was estimated that each year in the US, cSCCcauses between 4000 and 9000 deaths and bears a $4 billioneconomic burden [6]. While the risk of a single AK transfor-mation to cancer is overall low, patients typically have manyAKs or at least multiple fields of precancerous, photodamagedskin.

Understanding field cancerization is important for elucidat-ing the malignant transformation process from normal skin tocSCC. Determining the risk of cSCC development from asingle lesion as well as risk for a field may improve patientoutcomes by identifying those patients who would benefitmost from earlier treatment [2]. Herein, we discuss the emerg-ing research of field cancerization in dermatology, with em-phasis on the most recent research literature on the pathogen-esis, classification, and treatments of AKs.

Pathogenesis

Photodamage is caused by chronic ultraviolent (UV) radiationexposure from sunlight and is associated with detrimentalconsequences to the skin, such as atrophy and increased riskof cancer [13]. UVA irradiation (320–400 nm) is associated

with indirect damage to DNA by oxidative injury via reactiveoxygen species (ROS) [14]. UVB irradiation (290–320 nm)causes direct damage to DNA by inducing structural rear-rangements of nucleotides, such as thymidine dimerization,leading to physical distortions in the DNA strands [15]. Thecollective DNA damage and mutations over time interferewith replication and transcription, resulting in cutaneouscancerization of the field and clinically manifesting as varyingdegrees of photodamaged skin [16]. Field cancerization of theskin begins when UV radiation induces a sporadic somaticmutation in epidermal keratinocytes (Fig. 1) [1••].With chron-ic exposure to UV radiation, clonal expansion occurs and mu-tations accumulate, leading to AKs on sun-exposed skin [1••].As UV radiation non-selectively damages DNA, AKs mayhave varying mutations and may be at different stages of de-velopment [5]. The transformation of AKs to cSCC is thoughtto occur in a stepwise fashion with progressive developmentof epidermal neoplasia, which has been classified clinically byOlsen et al. and histologically by Rowert-Huber et al. [17, 18].For clinical research purposes, AKs are graded based on thick-ness and the degree of hyperkeratosis: AK 1 is better palpatedthan visualized, AK 2 is visible, and AK 3 is hyperkeratotic[17]. Histologically, AKs are graded based on the extent ofepidermal atypical keratinocytes: AKI is limited to epidermalbasal layer, AKII extends to the lower two thirds of the epi-dermis, and AKIII involves the full epidermal thickness [18].Histologically graded AKI was recently found to be the mostcommon precursor to cSCC as progression occurs throughdirect invasion from proliferating atypical keratinocytes, suchthat any grade of AKs may be invasive [19••].

In photodamaged skin, AKs, and cSCCs, evidence of theTP53 tumor suppressor protein was observed in keratinocytesand has been recorded in 69 to over 90% of invasive cSCC[20, 21]. Other implicated mutations in field-cancerizedislands include the oncogenes c-myc, Ras, H-ras, c-jun,WNT, and KNSTRN and the tumor suppressors, p16INK4,NF-κB, Notch1, Notch2, Hes1, and Erdr1 [2, 16, 20, 22, 23].Some studies have genotyped AKs and cSCC to identify po-tential key biomarkers which may be useful for diagnosis,prevention, or treatment [11, 24, 25].

Since AKs and cSCC share many genetic features, AKs areused as a risk marker for cSCC; however, there is emergingevidence that AKs may also herald other types of skin cancer[1••]. One study found evidence of histologically present AKsin 57% (35/61) of cSCC specimens, 33% (21/64) of basal cellcarcinoma specimens, and 25% (6/24) of malignant melano-ma specimens [1••]. The extent of field damage may be evenlarger than reported as only 0.1 mm of the distal lateral marginwas assessed for discontiguous foci of dysplasia [1••]. Therelationship between AKs and other cutaneous malignanciesis unclear, but these findings are significant as they suggestthat any cutaneous malignancy may be surrounded by anexpanding pre-neoplastic field [1••]. Another study

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demonstrated a 42% risk of developing subsequent cSCCwithin 5 years of the original diagnosis and a 72% increasein risk if the patient had two or more cSCCs at the initial timeof diagnosis [2, 26]. Thus, a patient with a known diagnosis ofcSCC is at increased risk of developing additional cSCCs.

AK Classification

The wide variety of clinical and histological presenta-tions of AKs presents a challenge to developing a uni-form grading system that predicts whether a lesion willregress or progress. Grading of AKs based on thicknesswas found to be inconsistent among experts [5, 17].Grading based purely on histology is not specificenough as histological findings may overlap with otherkeratinocyte diseases such as Bowen’s disease and seb-orrheic keratosis [18]. Additionally, there is no evidenceto support that the stepwise progression from AKI toAKIII is necessary for the transformation of atypicalkeratinocytes into cSCC [27]. Other classificationschemes based on lesion size, number of lesions, andhistological findings are focused on individual lesions,an approach that does not consider the process of fieldcancerization and spontaneous mutations [28].

In 2017, two scales were developed and validated to mea-sure AKs in the context of field cancerization, the ActinicKeratosis Area and Severity Index (AKASI) and the ActinicKeratosis Field Assessment Scale (AK-FAS) [29, 30]. TheAKASI evaluates AK parameters including severity on thehead, area of extent, and clinical features (i.e., distribution,erythema, and thickness) [29]. The AK-FAS is used to gradeAK severity based on AK area (as opposed to number oflesions), hyperkeratosis severity, and sun damage severity[30]. These scales are not widely used in the clinical setting,possibly due to their recent introduction.

One of the major issues with grading is the hetero-geneous nature of field cancerization, which leads to avariety of grades within a single lesion [31]. Two thirds(67%) of AKs have more than one grade [31]. Thediverse grading within a lesion also means that histo-pathological information from one biopsy may not beextrapolated to the entire field. One solution is to clas-sify AKs based on their development; this requires abetter understanding of the role of field cancerizationin AK and cSCC development [27]. The predictive val-ue of field disarray in lesion progression also requiresfurther investigation as earlier identification of lesionswith malignant potential may result in better patientoutcomes and decrease the financial burden of thisdisease.

Fig. 1 Field cancerization theory. a Previous theory of cSCC formation. b Current field cancerization theory. UVultraviolet, cSCC cutaneous squamouscell carcinoma, AK actinic keratosis

124 Curr Derm Rep (2019) 8:122–132

Management/Treatment

The ideal management of field cancerization is throughpatient education on the importance of UV exposureavoidance (i.e., using high SPF sunscreen that protectsagainst UVA and UVB rays) to minimize photodamage[2]. Recently, oral nicotinamide (vitamin B3) has beenadvocated for use as skin cancer chemoprevention dueto its protective effects against UV-induced cutaneousdamage, reducing the rate of new AKs in high-risk pa-tients [32]. The therapeutic mechanisms of nicotinamideinvolve enhancement of DNA repair via blockade ofUV-induced ATP depletion [32]. This chemopreventativemethod may supplement behavioral modifications in pa-tients at higher risk of developing AKs.

If the patient has already developed AKs, then treatment isusually offered in routine clinical practice. As there is no reli-able way to determine which AKs will become cSCCs, theprevailing recommendation by expert consensus is to treat alllesions [2]. Treatment for AKsmay be lesion-directed or field-directed. Lesion-directed therapies are adequate for well-defined lesions and may be useful when complete clearanceis not achieved by other methods [33]. Recently, there hasbeen a shift toward field-directed therapy using topical agents,photodynamic therapy (PDT), chemical peels, laserresurfacing, etc. [34, 35•, 36]. Since field cancerization causesmultifocal areas of dysplasia and precancerous changes, a sin-gle diagnosis of cSCC signifies increased risk of subsequentcSCC and therefore may require long-term follow-up [2].Subsequent cSCC may be recurrence of the primary cSCCor may arise as a new primary cancer due to the heterogeneityof field cancerization (Fig. 2) [2]. Currently available field-directed therapies are being optimized and new field-directedtopical agents and laser therapies are discussed below. In

addition, Table 1 describes clinical trials currently being con-ducted in the US for AK treatment.

Currently Available

5-Fluorouracil and Imiquimod

5-fluorouracil (5-FU) and imiquimod are two topical agentsthat are well-established and commonly used for field-directedtherapies for AKs [37]. 5-FU is available in cream formulationwith 0.5%, 1%, and 5% strengths. The 5% cream is appliedtwice daily for 2 to 4 weeks whereas 0.5% and 1% creams areapplied daily for 3 to 4 weeks [38]. Imiquimod is available as3.75% and 5% creams. The 3.75% cream is applied once dailyfor 8 h for two 2-week treatment cycles separated by a 2-weekno-treatment period whereas the 5% cream is applied twotimes per week for 8 h for 16 weeks [39, 40].

More recent studies combine AK therapies, use differentconcentrations, or report rare adverse events [41–46].Combination therapy studies include 5% 5-FU and 0.005%calcipotriol, which was found to reduce the number of AKlesions by87.8%comparedwith 26.3% for 5%5-FUandwhitepetrolatum inmice [45]. This effectwas thought to be related toan activation of CD4+ T cell-mediated immunity [45].Different concentrations of imiquimod, 2.5% and 3.75%,werestudied in a meta-analysis of four phase III clinical trials [46].These doses are lower than the typical 5% imiquimod for use asshort-term cycle therapy or an expanded treatment area [46].The two concentrations showed dose-related effects onCombined Investigator’s Global Integrated Photodamagescore and both performed significantly better than the controlcream [46]. While 5-FU and imiquimod are considered safe,there have been recent case reports of rare adverse reactions.One report described fever, fatigue, mucositis, dehydration,and significant weight loss, thought to be related to adihydropyrimidine dehydrogenase deficiency, leading to de-creased drug clearance and systemic 5-FU accumulation after0.5% topical 5-FU [42].Another case report described a patientwith blistering, peeling, and painful erythema afteroverapplying the topical 5% 5-FU she was prescribed [44].

Photodynamic Therapy

PDT consists of topical application of a photosensitizingagent that is activated by light. In the case of aminolevulinicacid (ALA), one of the more commonly used photosensitizingagents in the US, precursors of the heme pathway are con-verted to protoporphyrin IX (PpIX) in the skin [47]. PpIXgenerates ROS when exposed to light irradiation, typicallyred or blue light, leading to cell death and an inflammatoryresponse [47]. Red light PDT has been a staple in EuropeanPDT and is being reintroduced to the US market. Red lightpenetrates deeper than other wavelengths of visible light andFig. 2 Field cancerization and local recurrences of tumors

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Table 1 Ongoing clinical trials for AK investigation in the USA. NA not available

Study title (identifier) Phase Interventions Study design Primary outcome(time frame)

PDT Daylight Photodynamic Therapy for ActinicKeratosis (NCT03322293)

1 Drug: ALATopical 20%Topical Solution

Device: BLU-U blue lightphototherapy illuminator

RandomizedSingle-blind

Reduction intreatmentsymptoms(12 weeks)

Protocols for Painless Photodynamic Therapy(PDT) of Actinic Keratoses

(NCT02124733)

3 Procedure: ALA-PDTwithaltered incubation time (0 vs1 h)

RandomizedSingle-blind

AK clearance(3 months)

Photodynamic Therapy Incubation Times forActinic Keratosis

(NCT03066843)

NA Drug: ALADevice: blue light therapy with

altered incubation time (0 vs1 h)

RandomizedSingle-blind

Change in number ofAK lesions(baseline and8 weeks)

DUSA: Cyclic PDT for the Prevention of AK &NMSC in Solid Organ Transplant Recipients

(NCT03110159)

1, 2 Drug: Levulan® Kerastick®Drug: BLU-U blue light

photodynamic therapy

Single-groupOpen-label

Primary preventionof AKs andNMSCs (3 years)

Time to occurrenceof AKs andNMSCs (3 years)

Biomarker Database Registry for PhotodynamicTherapy

(NCT03319251)

NA PDT NA AK clearance(3 months)

Vitamin D levels(baseline)

VDA-1102:anti-neoplasticagent

Study to Evaluate the Efficacy, Safety, andTolerability of Topical VDA-1102 Ointment inSubjects With Actinic Keratosis (Phase2b)

(NCT03538951)

2 Drug: 10% VDA-1102Drug: 20% VDA-1102

Open-labelMulti-center

Complete clearancerate (16 weeks)

Complete facialclearance rate(16 weeks)

SOR007: uncoatednanoparticulatepaclitaxelointment

Study of SOR007 Ointment for Actinic Keratosis(NCT03083470)

2 Drug: SOR007 (uncoatednanoparticulate paclitaxel)Ointment: 0.15%, 1.0%,2.0%

Other: SOR007 ointmentvehicle

RandomizedDouble-blind

Incidence oftreatmentemergent adverseevents (28 days)

SR-T100:antiproliferativeagent

Efficacy and Safety Phase II Study of SR-T100 toTreat Actinic Keratosis

(NCT01516515)

2 Drug: vehicle gelDrug: SR-T100 with 2.3% of

SM

RandomizedDouble-blind

Total clearance rate(24 weeks)

KX2-391: Srctyrosine kinaseinhibitor

A Ph2a, Open-Label, Multicenter, Activity &Safety Study of KX2–391 Oint in Subj. wActinic Keratosis on the Face or Scalp

(NCT02838628)

2 Drug: KX2-391 Single-groupOpen-label

Complete responserate (57 days)

A Multi-Center Study to Evaluate the Efficacyand Safety of KX2–391 Ointment 1% on AKon Face or Scalp (AK003)

(NCT03285477)

3 Drug: KX2-391 ointment 1%Drug: placebo

RandomizedDouble-blindMulti-center

Complete responserate (57 days)

A Multi-Center Study to Evaluate the Efficacyand Safety of KX2–391 Ointment 1% on AKon Face or Scalp (AK004)

(NCT03285490)

3 Drug: KX2-391 ointment 1%Drug: placebo

RandomizedDouble-blindMulti-center

Complete responserate (57 days)

5-FU Evaluating Skin Appearance Following5-Flourouracil Cream for Treatment of ActinicKeratosis and the Effects of Topical Agents

(NCT03279328)

4 Drug: topical steroid ointmentOther: VaselineDrug: skin barrier moisturizer

RandomizedOpen-label

Skin barrierbiophysicalproperties (2 h)

CAP Using a Cold Atmospheric Plasma Device toTreat Skin Disorders

(NCT02759900)

NA Device: non-thermal,atmospheric plasma

Single-groupOpen-label

Clinicalimprovement(1 month)

Other Validation of SHADE a Mobile Technology forMonitoring of Ultraviolet Exposure

(NCT03315286)

NA Device: SHADE UltravioletSensor

Behavioral: Standard of carecounseling

RandomizedDouble-blind

Quantification of AK(6 months)

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has a higher fluence rate compared to blue light; this maycause more pain during light treatment [48, 49]. PDT hasminimal downtime although patients become more sensitiveto light, which warrants precaution for sun exposure and med-ications that cause photosensitivity [50, 51]. There is evidencethat PDT may be able to correct dysplastic, photodamagedskin by altering cancer-associated gene expression [52••].PDT has been reported to have desirable cosmetic effectswhen used to treat AKs through activation of processes in-volved in wound healing [52••, 53]. A phase III study usingALA and red light to treat an entire field found long-lastingskin rejuvenation in areas of asymptomatic photodamage inaddition to being effective for the treatment of mild-to-moderate AK lesions [53].

PDTmay not be as effective for AKs on the extremities dueto the thermal dependence of endogenous PpIX generation[54••]. However, thermal PDT, which uses higher tempera-tures during incubation of the photosensitizer, results in betteroutcomes in field treatment of the extremities, shorter incuba-tion times, and does not increase side effects [54••, 55–57,58••]. Higher temperatures were achieved by wrapping theextremity tested with a heating pad to set “medium” whichachieved maximal temperatures ranging from 37.2 to 43.4 °Cduring incubation compared with a baseline of 29.6 to 33.6 °C[54••].

Since patients may experience discomfort during PDT, var-ious strategies have been studied to mitigate this adverse ef-fect, use of including of alternate light sources, pretreatments,and different photosensitizers. A variation to conventionalPDT is to use daylight as an alternative light source to activatePpIX [59–61]. This method allows continuous and gradualactivation of the photosensitizer with daylight rather than withred or blue light, resulting in decreased pain while still main-taining clearance rates similar to conventional PDT [59–65].Metal halide white light may be an alternative to daylight PDT[66]. This therapeutic option is significant as daylight PDT isdependent on weather conditions and requires patient abilityto go outside for light exposure. Other methods to reduce paininclude a two-step irradiance treatment and using green lightdue to its decreased depth of tissue penetration [67, 68].

Recent investigations are evaluating combination thera-pies, comparing PDT protocols, and developing new photo-sensitizers. Microneedling as a pretreatment decreased ALAincubation time and decreased pain with similar efficacy to theconventional 1-h ALA incubation time method [69•].Microneedling may assist with drug delivery as it may createmicrochannels to bypass the stratum corneum [69•].Calcipotriol, a synthetic vitamin D derivative, may be usedbefore PDT [70]. Patients undergoing PDT who werepretreated with calcipotriol were found to have fewer sideeffects and a higher clearance rate of AKs compared to thosewho received PDT only [71–73]. Calcipotriol pretreatment isthought to boost the amount of PpIX in the skin, thereby

enhancing efficacy of field treatment [72]. Vignion-Dewalleet al. recently published a comprehensive in silico analysis ofvarious PDT protocols using different lights to determine theregimen that offers the best complete response rate at 3 months[74••]. The following top four protocols performed similarly:daylight PDT on a clear sunny day, daylight PDT on an over-cast day, PDTwith white LED lamp, and PDTwith blue light[74••]. The development of new photosensitizers may becoupled with light therapy to form an alternative treatment.One example is photochemical internalization in which anamphiphilic photosensitizer along with a cytotoxic moleculeor ribosomal-inactivation protein is given [75]. The cytotoxiccompound is taken up into the cell and with light exposure,causes death by endosome rupture. Photochemical internali-zation is being studied in head and neck cancers but has notyet been reported for use in skin cancer [76].

Needed to Study

SR-T100

SR-T100 gel, not to be confused with the radiotherapy SRT-100, is a topical antiproliferative agent, with active ingredientssolamargine, solasodine, and solasonine, thought to treat AKsthrough modulation of the tumor necrosis factor receptor sig-naling pathway [77]. A study in Taiwan reported 32% com-plete clearance rate and 72% partial clearance rate for thegroup receiving SR-T100 gel compared with 12% completeclearance and 37% partial clearance rate for the control group[78]. The odds ratio for complete clearance was 2.14 and 4.36for partial clearance [78]. The study gel was applied to an areathat covered the AK and then covered by an occlusive dress-ing for 8 h daily for 16 weeks. In terms of safety, the rate ofadverse events, 55.3% (42/76) for SR-T100 and 51.4% (19/37) for vehicle, and the rate of serious adverse events, 13.2%(10/76) for SR-T100 and 13.5 (5/37) for vehicle, were notstatistically different. Serious adverse events were concludedto be unrelated to the study drug. Rates of erythema, burning/stinging, and erosion were higher in the SR-T100 group com-pared to the vehicle group. While these initial results arepromising, more studies are necessary to evaluate the fieldeffects of this drug. SR-T100 is currently under investigationin a phase II clinical trial in the US (Table 1).

2,4,6-Octatrienoic Acid

2,4,6-octatrienoic acid is a parrodiene derivative that has beenshown to activate peroxisome proliferator-activatedreceptor-γ (PPARγ), reducing oxidative damage and inducingDNA repair enzymes thereby treating the field [79]. As far asthe authors know, this is the only study that has used this agentto treat AKs. Patients in a phase IV study applied a topicalcream containing 2,4,6-octatreinoic acid and urea twice daily

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for 2 months [80]. At the 3-month follow-up visit, 82.5% ofpatients achieved complete elimination of their AK lesions[80]. No side effects were reported although images providedin the article show common side effects such as erythema andcrusting [80]. Patients were followed clinically and thereforelack histologic confirmation of lesion treatment. Further re-search with longer follow-up, periods, side effect reporting,and confirmation of AK treatment are necessary for thisproduct.

Nonthermal Atmospheric Pressure Plasma

Nonthermal atmospheric pressure plasma, also known as coldatmospheric pressure plasma (CAP), is a new therapy beinginvestigated for treatment of AKs. CAP demonstrated thera-peutic potential in vitro and in animal models [81]. The mech-anism of action is not fully understood but is thought to berelated to ROS generation affecting cells undergoing DNAreplication (i.e., cancer cells) [81]. This modality involvesdirect cutaneous contact of ionized gas without thermal dam-age to the skin [81]. One study using 120 s of CAP therapytwice weekly for seven applications on seven patients withextensive AKs showed promising potential as it resulted inclinical improvement and rejuvenating effects without adverseevents or limitations on the maximum treatment area [82].Another case series of five patients treated 17 lesions; 1 monthafter a single treatment lasting 1 to 2 min, nine lesionscompletely resolved, three improved significantly, and fiveshowed no major changes [83•]. Additionally, no side effectswere noted [83•]. There is currently one study underway eval-uating a CAP device for the treatment of various skin disor-ders, including AKs (Table 1). The preliminary results usingCAP as a therapy for AKs are encouraging but more researchis needed to study the mechanism, efficacy, safety, and opti-mal protocol for CAP.

Lasers

Cutaneous laser resurfacing may be used on an entire skinfield to induce new collagen formation and remodeling.Fractional lasers target evenly spaced microthermal zones tominimize thermal damage [84]. Ablative lasers function athigher wavelengths to destroy the epidermis and dermis com-pared with nonablative lasers [35•].

Lasers are being investigated as monotherapy and as ad-junctive applications in AK treatment [84]. One split-facestudy using ablative fractional laser (AFXL) therapy com-pared to no treatment for AKs found a significant reductionof AKs at 1 month; however, at the 3-month follow-up, reduc-tion of AKs on either side of the face was similar due tospontaneous regression on the non-treated side [85]. In thisstudy, the Ultrapulse CO2 laser ActiveFX handpiece(Lumenis) was used with the settings 70 mJ per pulse, power

at 9 W, and density of 4 [85]. In porcine skin, treatment withAFXLwas found to inducemore dermal deposition of ingenolmebutate [86]. Another study using AFXL in human 3D AKskin equivalents improved MAL uptake and improved PDToutcomes [87]. Fractional Q-switched 1064-nm Nd:YAG la-ser, a non-ablative laser typically used for tattoo and pigmenttreatment, is being studied for AK treatment [88]. After foursessions, complete clearance was observed in five out of sixpatients at the 3-month follow-up [88]. Evidence thus far ap-pears to favor lasers as an adjunct to current therapies as theymay facilitate delivery of topical agents, although the idealmonotherapy laser and settings have not been clearly definedyet.

Er:YAG ablative fractional laser-assisted MAL-PDT(AFL-PDT) as a combination therapy has shown positive re-sults [89]. AFL-PDT was found to have an 84.8% responserate at 12 months and a 7.5% recurrence rate which was sig-nificantly better than the MAL-PDT only group with a 51.1%response rate and 22.1% recurrence rate [89]. Interestingly, nosignificant differences in pain were found across the treatmentgroups [89]. Another study found fractional CO2 followed byALA-PDT to produce significantly higher clearance rates thanALA-PDT alone, 89.8% versus 71.2% at 12 weeks and bettercosmesis as rated by the investigator and patients [90]. Interms of side effects, the laser group experienced slightly moreintense pain and prolonged erythema [90]. Laser use for thetreatment of AKs has shown favorable results but more studiesare needed to determine efficacy and safety in a larger numberof patients as well as determine how lasers best fit in the field-directed AK treatment algorithm.

Chemical Peels

Chemical peels are another resurfacing technique, com-monly used for cosmetic purposes, that is being studiedfor AK therapy. It is applied topically to cause chemicalablation of the skin, causing the superficial layers toslough off, inducing regeneration of the epidermis anddermis. One study compared one session of either ALAPDT or 35% trichloroacetic acid (TCA) peel [91].Adverse events of TCA included persistent erythema,bacterial superinfection in one patient, and scarring insix patients [91]. Patients treated with ALA PDT demon-strated a complete clearance rate of 73.7% at the 12-month follow-up, compared with 48.8% in the TCAgroup [91]. Additionally, better Physician GlobalAssessment scores were noted with the MAL PDTgroup, with 54.5% of patients achieving completely clearor almost clear in target areas versus 11.8% in the TCAgroup [91]. Further studies with larger sample sizes,combination therapy with TCA, treatment confirmationwith histology, and preventative studies may be neededto assess the role of chemical peels in AK management.

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Conclusions

Cutaneous field cancerization describes the process by whichchronic UV exposure induces DNA damage and multifocaldysplastic cells. Genetic alterations, progressive invasion ofatypical keratinocytes, and crusty, scaly growths may be ob-served. As a result, recent advances in field cancerization re-search have furthered understanding of the underlying patho-physiology of AKs and cSCCs. Examining cancer develop-ment through a field approachmay lead to discoveries in otherdisease processes including basal cell carcinoma and melano-ma. Furthermore, field-directed therapy is desirable fortreating AKs as there are high recurrence rates of cSCC whentherapy is lesion-directed. PDT, topical treatments, and laserscontinue to be commonly employed therapies that are safe andefficacious. As current therapies for AKs are being optimizedand new treatments are being developed, we expect efficacyof field therapy to improve. The combination of laser andtopical treatments may enhance efficacy in the clinical setting.Comparing the genetic profile of pre- and post-AK treatmentareas may reveal important biomarkers for disease progressionor regression and allow for gene-targeted approaches.

Limitations of current research on field cancerization in-clude the heterogenous nature of these lesions which pose aproblem for classification methods, extrapolation of biopsyresults to other lesions, and successful treatment of cSCC.Many clinicians use cryotherapy, a lesion-directed therapy,and may less often use or study field approaches. There is anunmet need for a better classification system for AKs thatprovides clinical predictability of lesion progression. Futurestudies should further elucidate the pathogenesis of fieldcancerization. Factors that differentiate the AKs that transforminto cSCCs from those that remain benign or regress needfurther exploration. Finally, current and developing treatmentoptions for AKs are abundant and studies are necessary todetermine the safest and most effective therapies.

Field cancerizat ion explains the continuum ofphotodamaged skin to cutaneous cSCC. Understanding thisprocess will help guide future management such that patientsmay benefit the most.

Compliance with Ethical Standards

Conflict of Interest Alisen Huang, Evan Austin, Andrew Mamalis, andJared Jagdeo received grants from Sun Pharmaceutical Industries Ltd. Dr.Jagdeo also received personal fees from Biofrontera.

Julie K. Nguyen declares no conflict of interest.

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors.

Open Access This article is distributed under the terms of the CreativeCommons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /creativecommons.org/licenses/by/4.0/), which permits unrestricted use,

distribution, and reproduction in any medium, provided you give appro-priate credit to the original author(s) and the source, provide a link to theCreative Commons license, and indicate if changes were made.

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